Pharmacokinetics of fluconazole in pediatric patients

The pharmacokinetic properties of fluconazole were studied in more than 100 pediatric patients, including 12 premature neonates. The volume of distribution and the rate of elimination differed significantly from the values reported for adults. The volume of distribution varied with age, being greatest during the neonatal period (1.18 to 2.25 l/kg) and decreasing by young adulthood to a value similar to that reported for adults (0.7 l/kg). With the exception of neonates, fluconazole clearance was generally more rapid in children than in adults, with a mean plasma elimination half-life of just over 20 h for all pediatric age groups. In neonates, fluconazole was eliminated slowly, with a mean elimination half-life of 88.6 h at birth, 67.5 h approximately one week later and 55.2 approximately two weeks after birth. Fluconazole appeared to be well absorbed from the gastrointestinal tract. These pharmacokinetic results, taken in conjunction with the corresponding data for adults, provide a sound basis for establishing appropriate fluconazole dosage recommendations for pediatric patients.     

Serotonergic and catecholaminergic influence on thyroid function in the vervet monkey

Vervet monkeys were pharmacologically treated acutely and with repeated dose loading to alter serotonergic systems to assess the role of serotonin in the regulation of the hypothalamus-pituitary-thyroid axis. Acute L-tryptophan administration failed to alter basal levels of thyroid hormones but did decrease the TRH-induced TSH response. Repeated dose loading of tryptophan or 5-hydroxytryptophan increased blood serotonin and plasma T3 and decreased plasma TSH. The tryptophan hydroxylase inhibitor p-chlorophenylalanine yielded decreased blood serotonin, but did not affect plasma TSH, T4 or T3. The monoamine oxidase inhibitor chlorgyline also resulted in increased blood serotonin, but increased plasma TSH and T4 and decreased T3. These data may be explained by a unitary hypothesis involving central catecholaminergic, rather than serotonergic, control of TRH release. Chlorgyline may produce its effects predominantly by facilitating catecholaminergic stimulation of TRH release resulting in increased TSH and a consequent increase in T4. It is suggested that the effects of tryptophan and 5-hydroxytryptophan result from increases in serotonin levels in the thyroid gland to produce an increase in T3 with a compensatory decrease in TSH via negative feedback. The differences observed between the acute and repeated dose loading studies stress the need for both types of studies before drawing conclusions about the effects of pharmacological manipulations on hormonal levels.     

The treatment of experimental schistosomiasis with a combination of oxamniquine and praziquantel

The object of the study was to identify any potential therapeutic advantage in using the two antischistosomal drugs, oxamniquine and praziquantel, in combination rather than separately, in the treatment of schistosomiasis. The efficacy of the drugs was studied in albino mice with mature Schistosoma mansoni infections. It was found that the efficacy of combinations of the two drugs was markedly superior to that expected on the basis of a simple additive effect. The significance of this synergistic action is discussed in the context of schistosomiasis therapy in man.     

Differential activation of temporal cortex during sentence completion in schizophrenic patients with and without formal thought disorder

The neural correlates of processing linguistic context in schizophrenic patients with formal thought disorder (FTD) were examined. Six right-handed male patients with prominent 'positive' FTD were compared with six schizophrenic patients without FTD and seven volunteers, matched for cognitive and demographic variables. Functional magnetic resonance imaging (IMRI) was used to measure cerebral activation while subjects read and completed sentence stems out loud. During a GENERATION condition, subjects were required to generate a word which completed the sentence stem appropriately. During a DECISION condition, subjects selected and articulated one of two presented terminal words. A READING condition served as baseline. The three conditions were compared with each other. Regions activated were identified in each group, and between-group differences were detected using an ANCOVA. When GENERATION was compared with READING, FTD patients showed less activation in the right superior temporal gyrus than patients without FTD or controls, but greater activation in the left inferior frontal, inferior temporal and fusiform gyri. FTD patients also showed an attenuated right temporal response when GENERATION was compared with DECISION. This differential engagement of the right temporal cortex was independent of differences in the speed or accuracy of responses, whereas the left fronto-temporal differences in activation were not evident after covarying for task errors. The attenuated engagement of right temporal cortex, which is implicated in language comprehension at the discourse level, is consistent with neuropsychological evidence linking thought disorder with deficits in processing linguistic context.     

Functional frontalisation with age: mapping neurodevelopmental trajectories with fMRI

The aim of this study was to investigate whether previously observed hypofrontality in adolescents with attention deficit-hyperactivity disorder (ADHD) during executive functioning [Rubia K, Overmeyer S, Taylor E, Brammer M, Williams S, Simmons A, Andrew C, Bullmore ET. Hypofrontality in attention deficit hyperactivity disorder during higher order motor control: a study using fMRI. Am J Psychiatry 1999;156(6):891-896] could be attributed to delayed maturation of frontal cortex. Brain activation of 17 healthy subjects, 9 adolescents and 8 young adults, during performance of a motor response inhibition task and a motor timing task was measured using functional magnetic resonance imaging (fMRI). The effect of age on brain activation was estimated, using the analysis of variance and regression, at both voxel and regional levels. In the delay task, superior performance in adults was paralleled by a significantly increased power of response in a network comprising prefrontal and parietal cortical regions and putamen. In the stop task, alternative neuronal routes--left hemispheric prefrontal regions in adults and right hemispheric opercular frontal cortex and caudate in adolescents--seem to have been recruited by the two groups for achieving comparable performances. A significant age effect was found for the prefrontal activation in both task, confirming the hypothesis of a dysmaturational pathogenesis for the hypofrontality in ADHD.     

Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair.

PURPOSE: It is known that blockage of epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K) activity enhances radiation sensitivity of human tumor cells presenting a K-RAS mutation. In the present study, we investigated whether impaired repair of DNA double-strand breaks (DSB) is responsible for the radiosensitizing effect of EGFR and PI3K inhibition in K-RAS mutated (K-RAS(mt)) cells. EXPERIMENTAL DESIGN: The effect of the EGFR tyrosine kinase inhibitor BIBX1382BS (BIBX) on cellular radiosensitivity was determined in K-RAS(mt) (A549) and K-RAS(wt) (FaDu) cell lines by clonogenic survival assay. Radiation-induced phosphorylation of H2AX (Ser139), ATM (Ser1981), and DNA-dependent protein kinase catalytic subunit (DNA-PKcs; Thr2609) was analyzed by immunoblotting. Twenty-four hours after irradiation, residual DSBs were quantified by identification of gammaH2AX foci and frequency of micronuclei. RESULTS: BIBX reduced clonogenic survival of K-RAS(mt)-A549 cells, but not of K-RAS(wt)-FaDu cells, after single-dose irradiation. Analysis of the radiation-induced H2AX phosphorylation revealed that BIBX, as well as the PI3K inhibitor LY294002, leads to a marked reduction of P-H2AX in K-RAS(mt)-A549 and MDA-MB-231 cells, but not in K-RAS(wt)-FaDu and HH4ded cells. Likewise, radiation-induced autophosphorylation of DNA-PKcs at Thr2609 was only blocked in A549 cells by these two inhibitors and AKT1 small interfering RNA transfection. However, neither in K-RAS(mt) nor in K-RAS(wt) cells the inhibitors did affect radiation-induced ATM phosphorylation. As a consequence of inhibitor treatment, a significant enhancement of both residual DSBs and frequency of micronuclei was apparent only in A549 but not in FaDu cells following radiation. CONCLUSION: Targeting of the EGFR-dependent PI3K-AKT pathway in K-RAS-mutated A549 cells significantly affects postradiation survival by affecting the activation of DNA-PKcs, resulting in a decreased DSB repair capacity.     

A 10-year experience of complex liver trauma

BACKGROUND: Liver trauma is a relatively rare surgical emergency but mortality and morbidity rates remain significant. It is likely that surgeons outside specialist centres will have limited experience in its management; therefore best practice should be identified and a specialist approach developed. METHODS: Data collected from 52 consecutive patients over a 10-year interval were examined to identify best practice in the management of these injuries. RESULTS: The majority of injuries occurred as a result of road traffic accidents; 39 (75 per cent) of the 52 patients were stable at presentation to the referring hospital. In 36 patients (69 per cent) the liver injury was a component of multiple trauma. Ultrasonography, computed tomography or no radiological investigation was used in the referring hospital in 18 (35 per cent), 25 (48 per cent) and nine (17 per cent) patients respectively. Operative management was undertaken in the referring hospital in 26 patients (50 per cent). The overall mortality rate was 23 per cent (12 of 52 patients), and increased with increasing grade of severity. Eight of 26 patients managed surgically at the referring hospital died, compared with four of the 26 patients managed without operation (P not significant). The median time from arrival at the referring hospital to operation was 4 h for haemodynamically stable patients and 3 h for those who were haemodynamically unstable. CONCLUSION: Most patients with liver trauma can be managed conservatively. Operative management carried out in non-specialized units is associated with high mortality and morbidity rates. Abdominal injuries should raise a high index of suspicion of liver injury, and the data suggest that computed tomography of the abdomen should precede laparotomy (even in some haemodynamically unstable patients) to facilitate discussion with a specialist unit at the earliest opportunity.     

Attention Deficit/Hyperactivity Disorder (ADHD) Symptoms Predict Alcohol Expectancy Development

ABSTRACT

Objective: Positive alcohol expectancies and attention deficit/hyperactivity disorder (ADHD) are independent risk factors for adolescent alcohol problems and substance use disorders. However, the association of early ADHD diagnostic status, as well as its separate dimensions of inattention and hyperactivity, with alcohol expectancies is essentially unknown. Method: At baseline (i.e., Wave 1), parents of 139 6- to 9-year-old children (71% male) with (N = 77; 55%) and without (N = 62; 45%) ADHD completed structured diagnostic interviews of child psychopathology. Approximately two years later (i.e., Wave 2), children completed a Memory Model-Based Expectancy Questionnaire (MMBEQ) to ascertain their positive and negative expectancies regarding alcohol use. All children were alcohol naïve at both baseline and follow-up assessments. Results: Controlling for age, sex, IQ, as well as the number of Wave 1 oppositional defiant disorder (ODD) and conduct disorder (CD) symptoms, the number of baseline hyperactivity symptoms prospectively predicted more positive arousing (i.e., MMBEQ “wild and crazy” subscale) alcohol expectancies at Wave 2. No predictive association was observed for the number of Wave 1 inattention symptoms and alcohol expectancies. Conclusions: Childhood hyperactivity prospectively and positively predicted expectancies regarding the arousing properties of alcohol, independent of inattention and ODD/CD symptoms, as well as other key covariates. Even in the absence of explicit alcohol engagement, youths with elevated hyperactivity may benefit from targeted intervention given its association with more positive arousing alcohol expectancies.     

Bevacizumab confers additional advantage to the combination of trastuzumab plus pertuzumab in trastuzumab-refractory breast cancer model

Purpose

We investigated antitumor activity of trastuzumab (T)/T-DM1 + pertuzumab (P) + bevacizumab (B) in T-sensitive (BT474) and T-resistant (BT474HerR) BC models in order to test whether or not the addition of an anti-angiogenic drug can provide a supplementary advantage to the antitumor activity of double HER2–mAB combination.

Methods

In addition to the antitumor activity (xenograft model), we tested antiproliferative effect, and HER2-mediated signals of different antibodies (T or P or T-DM1) in HER2-amplified T-sensitive, T-resistant and HER2-amplified/PIK3CA mutated (HCC1954) BT cell lines by 3D ON-TOP clonogenic growth assay and Western blots.

Results

Data show (1) T, T-DM1 or P blocked p-AKT (>60 %), p-ERK (>50 %) following heregulin in only T-sensitive cells, (2) T/T-DM1 + P, T/T-DM1 + B, and P + B reduced tumor growth as compared to any single-agent treatment, (3) T + P + B achieved almost complete regression of tumor growth, decreased cell proliferation, and inhibited tumor-induced angiogenesis, in both models, (4) antitumor activity of T + P + B was associated with the pharmacodynamic knockdown of p-AKT, and (5) T-DM1 + P caused complete regression of tumor volume in both models.

Conclusions

Our data demonstrate that B imparts a significant advantage when combined with T + P in the resistant model, in contrast to T-DM1 + P, as the triple combination of T-DM1 + P + B and the double combination of T-DM1 + P showed a comparable antitumor activity. Our study reveals the preclinical evidence in favor of the inclusion of B when combined with T + P in T-resistant BC patients.